There is a fundamental gap in our knowledge as to why lentiviruses, such as the human immunodeficiency virus type 1 (HIV-1), enter latency and whether latency plays any role in the natural history of infection. This information is critically needed to identify the mechanism of resilience of the latent reservoir. HIV-1 has killed 30 million people worldwide, 36 million people are living with HIV-1/AIDS, and there is no effective vaccine for HIV-1. The available antiretroviral therapies (ARTs) for treating HIV-1 cannot cure infected patients because HIV-1 enters a dormant state by latently infecting CD4+ T cells. The resulting latent reservoirs are long lived, ensuring lifelong persistence of the virus, and are recognized as the greatest obstacle to an HIV-1 cure. The prevailing and accepted view is that latency is an accident manifested by ART and carries no fitness benefit for the virus in the natural history of infection (i.e., it is not an evolved trait of the virus). However, there is no evidence to supportthis view that latency is an accident and alternative therapy strategies might be more effective than current strategies if latency provides a fitness benefit for the virus. The long-term goal is to design alternative therapy strategies to address the problem of HIV-1 latency. The immediate objective of this proposal is to determine if latency provides a fitness benefit for HIV-1. Based o recent studies showing that initial infection at the mucosal membrane is a harsh environment for the virus, our central hypothesis is that latency confers a selective advantage for the virus by protecting it against harsh conditions during initial infection at mucosal membranes. The rationale for this project is that the knowledge acquired will help to identify new therapeutic approaches. To achieve our objective, we will develop a multi- scale quantitative model linking latency to virus transmission and test this model in a novel experimental cell- culture system. The proposed research will break new ground in the long-term HIV latency problem. It will be the first effort to apply modern theoretical tools of viral evolution to test a fitness role for HI-1 latency. This contribution is significant, because if latency confers a fitness advantage to HIV-1, current eradication strategies are fighting an evolved viral phenotype, which is likely to be exceptionally challenging. Determining if latency is an evolved trait it would substantially alter HIV-1 cure research from eradication (e.g. 'activate-and-kill' approaches) to containment strategies (which could represent a 'functional cure').